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Mrna Expression of KIFIA, KIFIB, KIF2, KIF3A, KIF3B, KIF4, KIF5, and Cytoplasmic Dynein During Axonal Regeneration

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Mrna Expression of KIFIA, KIFIB, KIF2, KIF3A, KIF3B, KIF4, KIF5, and Cytoplasmic Dynein During Axonal Regeneration The Journal of Neuroscience, January 1, 1996, 76(1):31-35 mRNA Expression of KIFIA, KIFIB, KIF2, KIF3A, KIF3B, KIF4, KIF5, and Cytoplasmic Dynein during Axonal Regeneration Reiko Takemura,‘,’ Takao Nakata,’ Yasushi Okada,’ Hiroto Yamazaki,’ Zhizeng Zhang,’ and Nobutaka Hirokawa’ ‘Department of Anatomy and Cell Biology, School of Medicine, University of Tokyo, Hongo, Bunkyo-ku, Tokyo 113, Japan, and 20kinaka Memorial Institute for Medical Research, Toranomon, Minato-ku, Tokyo 105, Japan Mouse brain expresses multiple kinesin superfamily proteins brain but not in the adult, were under the detection limit in (KIFs), which are involved in vesicle transport. The expres- both control and regenerating dorsal root ganglion cells. sion of KlFs is developmentally regulated, and both the Because mRNA of neither KIF2 nor KIF4 increased signifi- mRNA and proteins of KIF2 and KIF4 are expressed abun- cantly, the results suggest that the gene expression of KlFs dantly in the juvenile brain. To elucidate the role of individual during regeneration does not recapitulate the embryonic kinesin superfamily motor proteins during regenerative out- development and support the hypothesis that different series growth of axons, we examined the mRNA expression of of events take place during the regenerative and embryonic KlFlA, KIFlB, KIF2, KIF3A, KIF3B, KIF4, and KIF5 in adult outgrowths of axons. In contrast, mRNA for cytoplasmic mouse dorsal root ganglion cells after sciatic nerve crush. dynein was slightly increased, up to 140%. This is consistent Seven to fourteen days after the nerve crush, the mRNA with the hypothesis that retrograde transport plays critical expression pattern of neurofilament and p-tubulin isotypes roles in regeneration such as the transport of neurotrophic suggested that the regenerative outgrowth of axons was factors. active. At these stages, levels of mRNA for KIFl A, KIFlB, KIF2, KIF3A, KIF3B, KIF4, and KIF5 were .50-80% of control. Key words: K/F; kinesin; cytoplasmic dynein; axon transport; The levels of mRNA for KIF4, which are detected in juvenile regeneration; neuron In the axon, various membraneorganelles are transported along mains are quite distinct, and they are all derived from distinct the microtubulesboth anterogradely and retrogradely (Hirokawa, genes. KIFlA is homologousto C. elegans uncl04 and is an 1993). Kinesin and cytoplasmic dynein have been identified as anterograde motor for transport of synaptic vesicle precursors motor proteins for the transport (Brady, 1985; Vale et al., 1985; (Okada et al., 1995a).On the other hand, KIFlB wasshown to be Paschalet al., 1987;Hirokawa, 1993). Kinesin has been shownto an anterogrademotor for mitochondria transport (Nangakuet al., be involved in the anterogrademovement and cytoplasmicdynein 1994).KIF5 appearsto be an isotype of kinesin heavy chain but is in the retrograde movement. However, within an axon many expressedalmost exclusively in the brain. KIF3A and KIF3B form different populations of membrane organelles are transported, a heterotrimer with associatedproteins (KAP3) and work as an and it is likely that moleculesother than kinesin and cytoplasmic anterograde motor for membranousorganelles (Kondo et al., dynein are involved in the regulation of the complex traffic of 1994; Yamazaki et al., 1995). KIF2 is unique in having its motor membraneorganelles within the axon. domain in the middle of the moleculeand is expressedabundantly Recently, we have cloned membersof kinesin superfamilypro- in juvenile neurons and transports membranousorganelles dis- teins (KIFs) from mouse brain. Five membersoriginally were tinct from synapticvesicle precursors not carried by kinesin heavy cloned (Aizawa et al., 1992;Hirokawa, 1993).Subsequent studies chain and KIF3A/B (Noda et al., 1995). All other membershave revealed that there are at least sevenmembers in the superfamily, motor domains at the N-terminal end. Multiple membersap- namely, KIFlA, KIFlB, KIF2, KIF3A, KIF3B, KIF4, and KIF5 peared to be expressedin the sameneuronal cells as shownby in (Kondo et al., 1994; Nangaku et al., 1994; Sekine et al., 1994; situ hybridization and immunocytochemistry,suggesting that dif- Noda et al., 1995; Okada et al., 1995a;Yamazaki et al., 1995). ferent membersplay different roles in axoplasmictransport within They all share the kinesin motor domain, which contains a puta- a singlecell. tive ATP-binding site and a microtubule-bindingsite. Other do- The changesin the gene expressionof neurofilament and tu- bulin during axonal regeneration of the mammalianperipheral Received Aug. 28, 1995; accepted Sept. 19, 1995. nerve systemhave been well studied (Hoffman et al., 1987; Hoff- This work was suooorted bv a Grant-in-Aid for a soecial oroiect research from the man and Cleveland, 1988;Miller et al., 1989;Wong and Oblinger, Ministry of Educati’dn, Scienle and Culture of Japan’(N.H,j. tie thank Dr. Nicholas J. Cowan for providing us with cDNAs for MP2, M/34, M/35, and NF68; Dr. Yasushi 1990; McKerracher et al., 1993). Particularly, it has been shown Harihara for valuable advice about surgical procedures on rodents, which was critical that the geneexpression of neurofilamentand tubulin recapitulate for starting up the experiments; and Dr. Hitoshi Kanno for valuable advice on Northern blotting procedures. We also thank Ms. Yukako Okamura, Atsuko the developmental pattern during regeneration. Therefore, the Kawaguchi, and Mihoko Watanabe for their excellent technical assistance. systemis suitablefor examiningthe role of certain proteins in the Correspondence should be addressed to Dr. Nobutaka Hirokawa, Department of elongation of axons. To elucidate the role of different motor Anatomy and Cell Biology, School of Medicine, University of Tokyo, 7-3-l Hongo, Bunkyo-ku, Tokyo 113, Japan. proteins during regeneration,we examinedthe geneexpression of Copyright 0 1995 Society for Neuroscience 0270-6474/95/160031-05$05.00/O seven membersof kinesin superfamily proteins, KIFlA, KIFlB, 32 J. Neurosci., January 1, 1996, 76(1):31-35 Takemura et al. KIF Expression and Regeneration P TUBULIN NF68 II IV I c r c r c r c r 2.4 - Figure 1. Northern hybridization autoradiograms of mouse DRG RNA probed with p-tubulin isotypes and NF68. Seven days after nerve crush, RNA was isolated from L4 and L5 DRG. The same amount of RNA was loaded for each set of control (c) and regenerating (r) lanes. Each filter was hybridized with probes for class II, IV, or I P-tubulin, or NF68. Ten micrograms of RNA were used for class II /3-tubulin, and 2 pg each for class I and IV /.?-tubulins and NF68. The numbers on the Zef indicate the size of the marker RNA in kilobases. KIF2, KIF3A, K.IF3B, KIF4, and KIF5, and cytoplasmicdynein, in fi-tubulin to standardize the variability of the amount of RNA loaded for mouselumbar dorsal root ganglion cells (DRG) during regener- the control and regenerating lanes. Probes. The 3’-noncoding regions of MP2, MP4, and MP5 and the ation by Northern hybridization. coding region of NF68 were gifts from Dr. N. J. Cowan of the Depart- ment of Biochemistry, New York University Medical Center (Lewis and MATERIALS AND METHODS Cowan, 1985; Lewis et al., 1985). For detection of KIFs, in addition to the Surgical operation. Surgical procedures performed for rats (Hoffman and probes described previously (Aizawa et al., 1992), a 630 bp fragment from Cleveland, 1988) were modified and adopted for mice. Namely, 7-week- the C-terminal tail region of KIFlA, the whole length of KIFlB, a 1.2 and old male C57BL mice weighing -20 gm were treated with sodium a 1.1 kb fragment from C-terminal tail regions of KIF3A and KIF3B were pentobarbital (6 mg/kg) and anesthetized with ether. Then the sciatic used. For the detection of cytoplasmic dynein, a 916 bp fragment of rat nerves were crushed bilaterally at the junction of I+4 and L5 spinal nerves cytoplasmic dynein from 6664 to 7580 (Zhang et al., 1993) was used. by tightly pinching the nerve twice for 30 set using No. 5 forceps. Femoral Quantification. After Northern hybridization, the filters were exposed and obturator nerves also were crushed in experiments in which the mice to Hyperfilm-MP (Amersham, Arlington Heights, IL) preflashed accord- were killed within 7 d after the operation. ing to a published method (Laskey, 1980) with an intensifying screen at RNA isolation. Seven and fourteen days after crushing the nerves, L4 -80°C. The results were quantified with a densitometer (Elscript 400, and L5 DRG were removed from mice and immediately frozen in liquid Hirschmann, Unterhaching, Germany) or imaging plates (BAS 2000, Fuji nitrogen. For each batch of RNA, -80 DRG were pooled and RNA was Film, Tokyo, Japan). isolated from DRG by acid guanidinium thiocyanate-phenol-chloroform extraction (Chomczynski and Sacchi, 1987). Control RNA was isolated in the same manner from L4 and L5 DRG of 7-week-old male C57BL mice. RESULTS Northern hybridization. The same amounts of total RNA obtained from Changes in mRNA expression of neurofilament and the control and regenerating mice were electrophoresed on 1% agarose gels containing formaldehyde and transferred to nitrocellulose filters. tubulin during regeneration in mouse DRG Two to ten micrograms of RNA was used, depending on the sensitivity of Changesin mRNA expressionof NF68 and classI, II, and IV the detection of the probes used. The filters were then hybridized with the /3-tubulins have been well documented in rat lumbar sensory probes labeled with [u-32P]dCTP using the random primer labeling neurons during axonal regeneration (Hoffman and Cleveland, method in a hybridization buffer at 42°C overnight. They were then washed to a final stringency of 0.1 X SSC, 0.1% SDS at 60°C for KIFs, 1 X 1988). Becausewe used similar surgical procedures,we first ex- SSC, 1% SDS at 60°C for p-tubulins, or 1X SSC, 1% SDS at 50°C for 60 aminedwhether similar changeswere seen in mice. As shownin min for cytoplasmic dynein probes. For a set of experiments using RNA Figure 1 and Table 1, the level of expressionof classII tubulin collected 7 d after nerve crush, each filter was rehybridized with class IV mRNA increased (1.4- to 4.7-fold), and that of NF68 mRNA decreased(40-60% of control) between7 and 14 d after crushing Table 1.
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